Genetic counseling: Coffin-Lowry Syndrome
Coffin-Lowry Syndrome Mode of Inheritance *X-linked dominant Chromosome Location *Xp22.2-p22.1 Molecular Genetics *Coffin-Lowry gene is a growth factor regulated serine-threonine kinase (RPS6KA3 or RSK) **Kinase activation in a number of pathways **Plays a role in stimulation of the cell cycle between G0 and G1 **Activates CREB (cAMP response element binding protein) ***Involved in neuronal survival ***Involved in conversion from short term to long term memory **Cells in patients with CLS have defective EGF stimulated phosphorylation of S6 *There are normal variants/polymorphisms *Normal gene product: ribosomal protein S6 kinase alpha 3 **Mutations in the RPS6KA3 give rise to CLS and XLMR Penetrance *In males with the disease-causing mutation: 100% will be affected *In females with the disease-causing mutation are carriers and are at high risk for developmental delay and mild physical signs of CLS Incidence and Carrier Frequency *No estimate of prevalance has been reported. **Estimate of A. Hunter et al., Children's Hospital Ontario: 1/40,000 to 1/50,000 Clinical Features *Growth Failure **Prenatally, growth is normal **Postnatal growth failure occurs early ***Males usually fall below 3rd percentile in height ***Microcephaly can be seen, but not in all cases *Dental Anomalies are common **Small teeth **Malpositioning **Hypodontia **Delayed eruption **Premature loss **Palate is high **Retrognathia in young children is replaced by prognathia *Neuropsychiatric **Patients are generally happy and pleasant **Severe MR occurs which may inhibit detailed neurologic assessment **Neurologic findings: ***Loss of strength and muscle mass ***Both decreased and increased deep tendon reflexes ***Sleep Apnea ***Stroke ***Progressive spasticity ***Progressive paraplegia with loss of the ability to walk ****Due to calcification of the ligamenta flava ****And Congenital stenosis of the spinal canal ***"Drop Attacks" ****Affect 10-20% of patients ****Unexpected tactile or auditory stimuli/excitement trigger EMG silence in the lower limbs *Results in a brief collapse, but no loss of conciousness ****Frequency of attacks may cause the need for a wheelchair to prevent injury **Cardiovascular ***~14% of males and ~5% of females have cardiovascular disease ****Abnormalities of the mitral, tricuspid, and aortic valves ****Short chordae ****Cardiomyopathy ****Congestive heart failure ****Dilatation of the aorta and pulmonary artery ***Cardiac anomalies may contribute to premature death **Musculoskeletal ***Progressive kyphoscoliosis ****At least 47% of affected males have this (32% of females) ****Respiratory compromise can happen due to this **Hearing and Vision ***Some patients have been reported to have hearing loss (14/89 males and 1/22 females) ****Clustering of hearing loss in families may occur ***Significant vision problems are uncommon ****Cataracts, retinal pigment atrophy, and optic atrophy have been reported ****Incidence of chronic eyelid irritation may be increased **Miscellaneous Findings ***Singles cases: ****Rectal prolapse ****Uterine Prolapse ****Unilateral renal agenesis ****Pyloric stenosis ****Jejunal diverticuli ****Colonic diverticuli ****Popiteal ganglion ****Anteriorly placed anus ****Increased facial pigment ****Enlarged trachea Lifespan **Mortality ***Early mortality is increased in CLS ****13.5% of males/4.5% of females mean age of death 20.5 years ***Complicating factors include: ****Cardiac anomalies ****Panacinar emphysema ****Respiratory complications ****Progressive Kyphoscoliosis ****Seizure-associated aspiration Testing *Ribosomal S6 kinase enzyme assay **Performed on cultured fibroblasts or transformed lymphoblasts **Available on a clinical basis in males **Not as useful in females due to broad range of enzyme activity resulting from X-chromosome inactivation *Molecular Genetic Testing **Uses of testing ***Confirmatory diagnostic testing ***Carrier testing ***Prenatal diagnosis **Test Methods ***Mutation Scanning ****SSCP analysis (followed by squencing of abnormal exons) *Available on a clinical basis *In CLS patients, mutations were identified in 34% who had a clinical diagnosis *A negative study does not rule out the diagnosis of CLS ***Protein Truncation testing ****~60% of 71 mutations idenitifed caused protein truncation ****Western blot then sequencing of variants ****Performed on cultured lymphoblasts ****Is available clinically for affected males ***Linkage Analysis ****For families in which direct testing has not identified a mutation *Assesses probability that at-risk individuals have inherited a familial mutation ****Acurracy dependent on: *Accurracy of clinical diagnosis of CLS *Informativeness of genetic markers in the family ****Samples are required from multiple family members to perform analysis **Laboratories offering clinical testing ***Universite Louis Pasteur :Institut Genet Biologie Molec/Cellulaire Illkirch , France :Director: Pierre Chambon :Contact: Andre Hanauer, PhD :email: Email: andre@titus.u-strasbg.fr :phone: (+33) 3-88-65-34-00 fax: (+33) 3-88-65-32-46 :Methodology: Direct DNA analysis, Linkage, Enzyme Assay, Protein Analysis :Additional Testing Provided: Prenatal diagnosis **Laboratories offering research testing ***JC Self Research Institute :Center for Molecular Studies Greenwood, SC :Director: Charles Schwartz, MS, PhD :Contact: Cindy Skinner, RN :email: cindy@ggc.org :phone: (800) 939-1920 phone2: (864) 941-8115 fax: (864) 388-1707 :Description of Research: Mutational analysis using SSCP or DHPLC, is done on all exons of RSK2 in males suspected to have CLS. Contact prior to sending samples. Surveillance, Management, Treatment *No specific therapy for CLS *Need for development of communication skills and self-care *Vision and hearing testing is appropriate *Cardiac studies should be done in childhood **Repeated every 5-10 years *Monitor for the development of progressive kyphoscoliosis **Intervention to prevent progression is appropriate *Should be suspicion for narrowing of spinal canal **Attention to gait **Bowel/bladder habits **Expression of pain **Focal neurological changes **Clonus **Abnormal tendon reflexes **Awareness of "drop attacks" ***Allows early intervention to minimize occurrence of triggering stimuli **Trial of antiepileptic medication may be indicated *Significant social resources may be required to support women with CLS **Genetic counseling and testing should be offered to at-risk family members Differential Diagnosis ***Borjeson-Fossman-Lehmann Syndrome (BFLS) ****X-linked recessive disorder ****Severe MR ****Hand findings ****Short anteverted nose with thick septum ****Small nares ****Kyphoscoliosis ***Facial appearances similar to CLS: ****Williams Syndrome ****FG syndrome ****X-linked alpha-thalassemia MR Resources/Support **NINDH Coffin-Lowry Information Page ***www.ninds.nih.gov/health_and_medical/disorders/coffin_lowry.htm ***Coffin-Lowry Syndrome Foundation :3045 255th Avenue SE :Sammamish, WA 98075 :CLSFoundation@yahoo.com :http://clsf.info :Tel: 425-427-0939 (M-F after 6pm PST ***National Organization for Rare Disorders (NORD) :P.O. Box 1968 :(55 Kenosia Avenue) :Danbury, CT 06813-1968 :orphan@rarediseases.org :http://www.rarediseases.org :Tel: 203-744-0100 Voice Mail 800-999-NORD (6673) :Fax: 203-798-2291 ***National Institute of Child Health and Human Development (NICHD) :National Institutes of Health :Bldg. 31, Rm. 2A32 :Bethesda, MD 20892-2425 :NICHDClearinghouse@mail.nih.gov :http://www.nichd.nih.gov :Tel: 301-496-5133 800-370-2943 ***National Institute of Mental Health (NIMH) :6001 Executive Blvd. :Rm. 8184, MSC 9663 :Bethesda, MD 20892-9663 :nimhinfo@nih.gov :http://www.nimh.nih.gov :Tel: 301-443-4513 TTY: 301-443-8431 Depression Info: 800-421-4211 Anxiety Info: 88-88-ANXIETY (269-4389) Panic Info: 888-64-PANIC (64-72642) :Fax: 301-443-4279 ***The Arc of the United States :1010 Wayne Avenue :Suite 650 :Silver Spring, MD 20910 :Info@thearc.org :http://www.thearc.org :Tel: 301-565-3842 :Fax: 301-565-3843 or -5342 ***March of Dimes Birth Defects Foundation :1275 Mamaroneck Avenue :White Plains, NY 10605 :askus@marchofdimes.org :http://www.marchofdimes.org :Tel: 914-428-7100 888-MODIMES (663-4637) :Fax: 914-428-8203 Conclusions *Review session *Answer final questions *Give card Notes The information in this outline was last updated in April 2003. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling